Proton-pump inhibitors (PPIs) are a group of drugs whose main action is a pronounced and long-lasting reduction of gastric acid production. They are the most potent inhibitors of acid secretion available. The group followed and has largely superseded another group of medications with similar effects, but a different mode of action, called H2-receptor antagonists. These drugs are among the most widely sold drugs in the world, and are generally considered effective.[1] The vast majority of these drugs are benzimidazole derivatives, but promising new research indicates the imidazopyridine derivatives may be a more effective means of treatment.[2] High dose or long-term use of PPIs carries a possible increased risk of bone fractures.[3]

Specialty professional organizations recommend that people take the lowest effective dose possible to achieve the desired therapeutic result when using proton pump inhibitors to treat gastroesophageal reflux disease long-term.[5][6] In the United States, the Food and Drug Administration advises that no more than three 14-day treatment courses should be used in one year.[3]

The effectiveness of PPIs has not been demonstrated in every case, despite their widespread use for these conditions. For example, they do not change the length of Barrett's esophagus.[7] The most objective test to assess success of PPI therapy in patients with GERD is esophageal pH monitoring.

In general, proton pump inhibitors are well tolerated, and the incidence of short-term adverse effects is relatively low. The range and occurrence of adverse effects are similar for all of the PPIs, though they have been reported more frequently with omeprazole. This may be due to its longer availability and, hence, clinical experience. Common adverse effects include: headache, nausea, diarrhea, abdominal pain, fatigue, and dizziness.[8]

Long-term use of PPIs has been less studied than short-term use, and the lack of data makes it difficult to make definitive statements.[10]

Gastric acid is important for breakdown of food and release of micronutrients, and some studies have shown possibilities for interference with absorption of iron, calcium, magnesium, and Vitamin B12. With regard to iron and Vitamin B12 the data are weak and several confounding factors have been identified.[10] Reduction in calcium absorption has been especially concerning, which led the FDA to include a warning PPI drug labels in 2010.[10] Interference with magnesium absorption is accepted as a class effect and people who have low levels of magnesium as a result of PPI therapy are switched to H2-receptor antagonist drugs.[10]

Long-term use of PPIs is strongly associated with the development of benign polyps from Fundic glands (which is distinct from fundic gland polyposis); these polyps do not cause cancer and resolve when PPIs are discontinued. There is no association between PPI use and cancer[10] or pre-cancer.[11] There is concern that use of PPIs may mask gastric cancers or other serious gastric problems and physicians should be aware of this effect.[10]

Targeting the terminal step in acid production, as well as the irreversible nature of the inhibition, results in a class of drugs that are significantly more effective than H2 antagonists and reduce gastric acid secretion by up to 99%. ("Irreversibility" refers to the effect on a single copy of the enzyme; the effect on the overall human digestive system is reversible, as the enzymes are naturally destroyed and replaced with new copies.)

The lack of the acid in the stomach will aid in the healing of duodenal ulcers, and reduces the pain from indigestion and heartburn, which can be exacerbated by stomach acid. The lack of stomach acid, also called hypochlorhydria, is the lack of sufficient hydrochloric acid, HCl, which is required for the digestion of proteins and the absorption of nutrients, in particular vitamin B12 and calcium.

The PPIs are given in an inactive form, which is neutrally charged (lipophilic) and readily crosses cell membranes into intracellular compartments (like the parietal cell canaliculus) with acidic environments. In an acid environment, the inactive drug is protonated and rearranges into its active form. As described above, the active form will covalently and irreversibly bind to the gastric proton pump, deactivating it.

Potassium-competitive inhibitors are experimental drugs that reversibly block the potassium-binding site of the proton pump. Soraprazan and revaprazan block H+ secretion much more quickly than classical PPIs (within a half-hour).[12] The development of soraprazan, however, was discontinued in 2007.[13]

The rate of omeprazole absorption is decreased by concomitant food intake. In addition, the absorption of lansoprazole and esomeprazole is decreased and delayed by food. It has been reported, however, that these pharmacokinetic effects have no significant impact on efficacy.[14][15]

The elimination half-life of PPIs ranges from 0.5 to 2.0 hr, but the effect of a single dose on acid secretion usually persists up to three days. This is because of accumulation of the drug in parietal cellcanaliculi and the irreversible nature of proton pump inhibition.